Method of preparing pyrrolotriazin-4-one compound and method of preparing isothiocyanatoformic acid ester derivative that is a reactant used for preparing pyrrolotriazin-4-one compound

ABSTRACT

A method of preparing a pyrrolotriazin-4-one and a method of preparing the isothiocyanatoformic acid ester derivative which can be used as a reactant in that method of preparing a pyrrolotriazin-4-one. The method of preparing the pyrrolotriazin-4-one includes an addition step of an aminopyrrole derivative and the isothiocyanatoformic compound and a step of ring-closing reaction of a resulting adduct.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention relates to a method of preparing apyrrolotriazin-4-one compound and, more particularly, to a method ofproducing a pyrrolotriazin-4-one compound which includes a step ofaddition reaction between a thioisocyanate compound and a 2-aminopyrrolederivative and a step of ring-closing reaction of a resulting adduct.The present invention also relates to a method of preparing anisothiocyanatoformic acid ester derivative, which is preferably used inthe preparation of pyrrolotriazinone compounds.

[0003]2. Description of the Related Art

[0004] It has been known that compounds having a pyrrolotriazin-4-oneskeleton are useful for use in photosensitive materials, heat-sensitivematerials, color developing components in photographic materials, andprecursors of biologically active substances. Various derivatives havebeen synthesized.

[0005] Isothiocyanatoformic acid ester derivatives have been used asreactants in the synthesis of pyrrolotriazinone compounds. It has beenknown that isothiocyanatoformic acid ester derivatives can besynthesized by a procedure described in J. C. S. Perkin I, page 2644(1973). A preparation scheme of an isothiocyanatoformic acid esterderivative as described in the reference is shown below.

[0006] In the conventional preparation method described above, a hydroxyderivative represented by the general formula (2′) is added to ethylisothiocyanatoformate that has been formed by reacting potassiumisothiocyanate with ethyl chloroformate. However, a portion of the ethylisothiocyanatoformate decomposes before reacting with the hydroxyderivative represented by the general formula (2′), because reactivitybetween potassium isothiocyanate and ethyl chioroformate is high and theethyl isothiocyanatoformate that is formed is unstable. As a result,there arises a problem that unreacted hydroxy derivative remains,thereby lowering purity and yield of an intermediate represented by thegeneral formula (4′).

[0007] The intermediate represented by the general formula (4′) and theisothiocyanatoformic acid ester derivative represented by the generalformula (A′) (in which R′ represents a methyl group or an ethyl group)must be purified by crystallizationat a low temperature, that is, lowerthan −50° C. because of low melting points thereof. Therefore, therearises a problem that it is difficult to industrially produce theintermediate and the isothiocyanatoformic acid ester derivative at highpurity and high yield because of complexity of operations.

[0008] There is also a problem that, in cases where the number of carbonatoms of R′ in the intermediate represented by the general formula (4′)and the isothiocyanatoformic acid ester derivative represented by thegeneral formula (A′) is 3 or more, the intermediate and the derivativeare often in the form of oils. Therefore, it is difficult toindustrially produce the same at high purity and high yield in thisrespect also.

[0009] Also, problems arise because the isothiocyanatoformic acid esterderivative represented by the general formula (A′) prepared by theconventional preparation method described above has low purity, rangingfrom 50 to 60%, and tar components derived from by-products in thepreparation of the isothiocyanatoformic acid ester derivative are formedwhen pyrrolotriazin-4-one is synthesized using the isothiocyanatoformicacid ester derivative as a reactant without purifying. Consequently,operation properties and the yield of pyrrolotriazin-4-one are lowered.

SUMMARY OF THE INVENTION

[0010] An object of the present invention is to provide a novel methodof preparing a pyrrolotriazin-4-one compound, which method is capable ofsynthesizing a-compound having a pyrrolotriazin-4-one skeleton at highyield in a simple operation. Another object of the present invention isto provide a novel isothiocyanatoformic acid ester derivative, which canbe used preferably as a reactant for synthesis of a pyrrolotriazinonecompound, and to provide a method of preparing the isothiocyanatoformicacid ester derivative at high purity and high yield.

[0011] A means for solving the problems described above is as follows.

[0012] A method of preparing a pyrrolotriazin-4-one represented by thefollowing general formula (4). The method includes:

[0013] an addition step of reacting an aminopyrrole derivativerepresented by the following general formula (1) with a reactantrepresented by the following general formula (2) to form an adductrepresented by the following general formula (3), and a cyclization stepof cyclizing the adduct represented by the following general formula (3)to form the pyrrolotriazin-4-one represented by the following generalformula (4).

[0014] In the formulas; R¹ represents a hydrogen atom, an alkyl group,an aryl group, or a group capable of withdrawing. R² and R³ eachindependently represents a hydrogen atom, an alkyl group, an aryl group,a cyano group, a substituted sulfonyl group, a substituted carbonylgroup, or a halogen atom. R⁴ and R⁶ each independently represents analkyl group or an aryl group. R⁵ represents an alkyl group, an arylgroup, or a heterocyclic group.

[0015] Also provided is a method of preparing an isothiocyanatoformicacid ester derivative represented by the following general formula (2).The method includes a step of adding a chloroformic acid derivativerepresented by the following general formula (7) to an isothiocyanicacid salt represented by the following general formula (5) and a hydroxyderivative represented by the following general formula (6) to preparean intermediate represented by the following general formula (8).

[0016] Z represents a sodium atom or a potassium atom in the generalformula (5). R⁴ and R⁶ in the general formulas (6), (7) and (8)are asdefined for the general formula (2).

[0017] Further provided is a method of preparing theisothiocyanatoformic acid ester derivative represented by the generalformula (2). This method includes a step of preparing an intermediaterepresented by the following general formula (10) from an intermediaterepresented by the following general formula (8) and a compoundrepresented by the following general formula (9).

[0018] M represents an alkali metal atom, an alkali earth metal atom, analuminum atom, or a magnesium atom in the general formula (9) R⁴ and R⁶in general formula (10) are as defined in the general formula (2).

[0019] Another method of preparing the isothiocyanatoformic acid esterderivative represented by the general formula (2) includes a step ofreacting an intermediate represented by the following general formula(10) with an alkylating agent represented by the following generalformula (12) to prepare the isothiocyanatoformic acid ester derivativerepresented by the general formula (2).

[0020] X represents a halogen atom or SO₃Ar in the general formula (11).Ar represents a substituted or non-substituted aryl group. R⁵ in thegeneral formulas (11) and (12) is the same as that in the generalformula (2).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] One mode of the present invention is a method of preparing apyrrolotriazin-4-one compound represented by general formula (4), thesame beinga target substance and a 2-aminopyrrole derivative representedby the general formula (1) being a starting substance.

[0022] Another mode of the present invention is an isothiocyanatoformicacid ester derivative represented by general formula (2). Theisothiocyanatoformic acid ester derivative is preferably used as areactant in the preparation of the pyrrolotriazinone compound. Forexample, when the isothiocyanatoformic acid ester derivative representedby the general formula (2) in the present invention is added as areactant, the pyrrolotriazin-4-one can be prepared by an additionreaction and a cyclization reaction.

[0023] In the general formulas (1) to (4), R¹ represents a hydrogenatom, an alkyl group, an aryl group, or a group capable of withdrawing;and R² and R³ each independently represents a hydrogen atom, an alkylgroup, an aryl group, a cyano group, a substituted sulfonyl group, asubstituted carbonyl group, or a halogen atom.

[0024] Alkyl groups having a substituent and non-substituted alkylgroups are included in examples of the alkyl group represented by eachof R¹ to R³. The alkyl group may be straight-chain or branched, and mayhave an unsaturated bond. Examples of the substituent in cases where thealkyl group has a substituent include an alkoxy group, aryloxy group,alkoxycarbonyl group, aryloxycarbonyl group, aryl group, hydroxy group,and a halogen atom. An aryl group that is the substituent may be furthersubstituted with an alkyl group, an alkoxy group, a nitro group, a cyanogroup, a hydroxy group, or a halogen atom.

[0025] Examples of the alkyl group represented by each of R¹ to R³include a methyl group, trifluoromethyl group, ethyl group, butyl group,hexyl group, octyl group, 2-ethylhexyl group, decyl group, dodecylgroup, octadecyl group, propyl group, isopropyl group, isobutyl group,sec-butyl group, t-butyl group, pentyl group, 1-ethylpentyl group,cyclopentyl group, cyclohexyl group, isopentyl group, heptyl group,nonyl group, undecyl group, propenyl group, heptadecenyl group, t-octylgroup ethoxycarbonylmethyl group, butoxycarbonylmethyl group,2-ethylhexyloxycarbonylmethyl group, 1-(ethoxy carbonyl)ethyl group,2′,4′-diisopentylphenyloxymethyl group, 2′,4′-di-t-butylphenyloxymethylgroup, ethoxycarbonylethyl group, 2-ethylhexyloxycarbonyl group,butyldecyloxycarbonylethyl group, dibutylaminocarbonylmethyl group,dibenzylaminocarbonylethyl group, ethyloxycarbonylpropyl group,2-ethylhexyloxycarbonylpropyl group, 2,4-di-t-aminophenyloxypropylgroup, 1-(2′,4′-di-t-aminophenyloxy)propyl group,2,4-di-t-butylphenyloxypropyl group, acetylaminoethyl group,N,N-dihexylaminocarbonylethyl group,2,4-di-t-amyloxyethyloxycarbonylpropyl group,isostearyloxycarbonylpropyl group, 1-(2,4-di-t-pentylphenyloxy)propylgroup, 2,4-di-t-pentylphenyloxyethyloxycarbonylpropyl group,naphthyloxyethyloxycarbonylethyl group,N-methyl-N-phenylethyloxycarbonylethyl group, andmethanesulfonylaminopropyl group and the like.

[0026] Examples of the aryl group represented by each of R¹ to R³includearyl groups having a substituent and non-substituted aryl groups.Examples of the substituent in cases where the aryl group has asubstituent include an alkyl group, alkoxy group, aryloxy group, halogenatom, nitro group, cyano group, substituted carbamoyl group, substitutedsulfamoyl group, substituted amino group, substituted oxycarbamoylgroup, substituted oxysulfonyl group, alkylthio group, arylthio group,alkylsulfonyl group, arylsulfonyl group, aryl group, hydroxy group, acylgroup, acyloxy group, substituted sulfonyloxy group, substitutedaminocarbonyloxy group, and substituted phosphoryloxy group.

[0027] Examples of the aryl group represented by each of R¹ to R³include a phenyl group, 2-methylphenyl group, 2 -chlorophenyl group,2-methoxyphenyl group, 2-ethoxyphenyl group, 2-propoxyphenyl group,2-isopropoxyphenyl group, 2-butoxyphenyl group,2-(2-ethylhexyloxy)phenyl group, 2-octyloxyphenyl group,2-undecyloxyphenyl group, 2-trifluoromethylphenyl group,2-(2-ethylhexyloxy)-5-chlorophenyl group,2,2′-hexyloxy-3,5-dichlorophenyl group,3-(2,4-di-t-pentylphenoxyethoxy)phenyl group,2-(dibutylaminocarbonylethoxy)phenyl group, 2,4-dichlorphenyl group,2,5-dichlorophenyl group, 2,4,6-trimethylphenyl group, 3-chlorophenylgroup, 3-nitrophenyl group, 3-cyanophenyl group, 3-trifluoromethylphenylgroup, 3-methoxyphenyl group, 3-ethoxyphenyl group, 3-butoxyphenylgroup, 3-(2′-ethylhexyloxy)phenyl group, 3,4-dichlorophenyl group,3,5-dichlorophenyl group, 3,4-dimethoxyphenyl group, 3,5-dibutoxyphenylgroup, 3-octyloxyphenyl group, 3-(dibutylaminocarbonylmethoxy)phenylgroup, 3-(di-2-ethylhexylaminocarbonylmethoxy)phenyl group,3-dodecyloxyphenyl group, 4-chlorophenyl group, 4-cyanophenyl group,4-nitrophenyl group, 4-trifluoromethylphenyl group, 4-methoxyphenylgroup, 4-ethoxyphenyl group, 4-isopropoxyphenyl group, 4-butoxyphenylgroup, 4-(2-ethylhexyloxy)phenyl group, 4-isopentyloxyphenyl group,4-(octadecyloxy)phenyl group, 4-benzylphenyl group,4-aminosulfonylphenyl group, 4,-N,N-dibutylsulfonylphenyl group,4-ethoxycarbonylphenyl group, 4-(2-ethylhexyloxycarbonyl)phenyl group,4-t-octylphenyl group, 4-fluorophenyl group, 3-acetylphenyl group,2-acetylaminophenyl group, 2,4-di-t-pentylphenyl group,4-(2-ethylhexyloxy)carbonylphenyl group, 4 -methylthiophenyl group,4-(4-chlorophenylthio)phenyl, and hydroxyphenyl group,phenylsulfonylphenyl group, phenylsulfonyloxyphenyl group,phenylcarbonyloxyphenyl group, dimethylaminocarbonyloxyphenyl group,butylcarbonyloxyphenyl group and the like.

[0028] A group capable of withdrawing as represented by R¹ (hereinafterreferred merely to as an “withdrawing group”) means a group capable ofwithdrawing when the compound represented by the general formula (4) isreacted with another compound, for example, an oxide or the like of acolor developing agent , such as an aromatic primary amine. Thewithdrawing group is a halogen atom; an aromatic azo group; an alkylgroup capable of linking at a coupling position via an oxygen, nitrogen,sulfur or carbon atom; an aryl group or heterocyclic group; an alkyl orarylsulfonyl group; an arylsulfinyl group; an alkylaryl or heterocycliccarbonyl group; or a heterocyclic group capable of linking at a couplingposition via a nitrogen atom. Examples thereof include a halogen atom,alkoxy group, aryloxy group, acyloxy group, alkyl or arylsulfonyloxygroup, acylamino group, alkyl or arylsulfonamide group,alkoxycarbonyloxy group, aryloxycarbonyloxy group, alkylaryl orheterocyclic thio group, carbamoylamino group, arylsulfinyl group,arylsulfonyl group, five- or six-membered nitrogen-containingheterocyclic group, imide group, arylazo group and the like. An alkylgroup, aryl group or heterocyclic group contained in the withdrawinggroup may be further substituted with a substituent. In a case ofsubstitution with two or more substituents, the substituents may be thesame or different and the substituents may further have substituents.

[0029] More specifically, preferred withdrawing groups are a halogenatom (e.g. fluorine atom, chlorine atom, bromine atom) alkoxy group(e.g. ethoxy, dodecyloxy, methoxyethylcarbamoylethoxy, carboxypropyloxy,methylsulfonylethoxy, ethoxycarbonylmethoxy), aryloxy group (e.g.4-methylphenoxy, 4-chlorophenoxy, 4-methoxyphenoxy, 4-carboxyphenoxy,3-ethoxycarboxyphenoxy, 3-acetylaminophenoxy, 2-carboxyphenoxy), acyloxygroup (e.g. acetoxy, tetradecanoyloxy, benzoyloxy), alkyl orarylsulfonyloxy group (e.g. methanesulfonyloxy, toluenesulfonyloxy),acylamino group (e.g. dichloroacetylamino, heptafluorobutyrylamino),alkyl or arylsulfonamide group (e.g. methanesulfonamino,trifluoromethanesulfonamino, p-toluenesulfonylamino), alkoxycarbonyloxygroup (e.g. ethoxycarbonylxy, benzyloxycarbonyloxy), aryloxycarbonyloxygroup (e.g. phenoxycarbonyloxy), alkylaryl or heterocyclic thio group(e.g. ethylthio, 2-carboxyethylthio, dodecylthio, 1-carboxydodecylthio,phenylthio, 2-butoxy-5-t-octylphenylthio, tetrazolylthio), arylsulfonylgroup (e.g. 2-butoxy-5-tert-octylphenylsulfonyl), arylsulfinyl group(e.g. 2-butoxy-5-tert-octylphenylsulfinyl), carbamoylamino group (e.g.N-methylcarbamoylamino, N-phenylcarbamoylamino), five- or six-memberednitrogen-contaning heterocyclic group (e.g. imidazolyl, pyrazolyl,triazolyl, tetrazolyl, 1,2-dihydro-2-oxo-1-pyridyl), imide group (e.g.succinimide, hydantoinyl), and arylazo group (e.g. phenylazo,4-methoxyphenylazo) and the like. These groups may be furthersubstituted. Examples of the withdrawing group linked through a carbonatom include a bis-type coupler obtained by condensing a 4 eq. couplerwith an aldehyde or ketone. The withdrawing group may contain aphotographically advantageous group such as a developing inhibitor, adeveloping accelerator and the like.

[0030] The withdrawing group is preferably a halogen atom, an alkoxygroup, an aryloxy group, an alkyl or arylthio group, an arylsulfonylgroup, an arylsulfinyl group, or a five- or six-memberednitrogen-containing heterocyclic group capable of linking at thecoupling position via a nitrogen atom, and is particularly preferably anarylthio group.

[0031] Alkylsulfonyl, arysulfonyl and sulfamoyl groups are included inexamples of the substituted sulfonyl group represented by each of R² andR³.

[0032] Examples of the alkylsulfonyl group include a methylsulfonylgroup, ethylsulfonyl group, propylsulfonyl group, isopropylsulfonylgroup, butylsulfonyl group, hexylsulfonyl group, cyclohexylsulfonylgroup, octylsulfonyl group, 2-ethylhexylsulfonyl group, decanoylsulfonylgroup, dodecanoylsulfonyl group, octadecanoylsulfonyl group,cyanomethylsulfonyl group and the like.

[0033] Examples of the arylsulfonyl group include a phenylsulfonylgroup, 1-naphthylsulfonyl group, 2-naphthylsulfonyl group,2-chlorophenylsulfonyl group, 2-methylphenylsulfonyl group,2-methoxyphenylsulfonyl group, 2-butoxyphenylsulfonyl group,3-chlorophenylsulfonyl group, 3-trifluoromethylphenylsulfonyl group,3-cyanophenylsulfonyl group, 3-(2-ethylhexyloxy)phenylsulfonyl group,3-nitrophenylsulfonyl group, 4-fluorophenylsulfonyl group,4-cyanophenylsulfonyl group, 4-butoxyphenylsulfonyl group,4-(2-ethylhexyloxy)phenylsulfonyl group, and 4-octadecylphenylsulfonylgroup and the like.

[0034] An N-alkylsulfamoyl group, N-arylsulfamoyl group,N,N-dialkylsulfamoyl group, N,N-diarylsulfamoyl group andN-alkyl-N-arylsulfamoyl group are included in examples of the sulfamoylgroup, in addition to sulfamoyl groups.

[0035] Examples of the sulfamoyl group include an N-methylsulfamoylgroup, N-ethylsulfamoyl group, N-propylsulfamoyl group, N-butylsulfamoylgroup, N-hexylsulfamoyl group, N-cyclohexylsulfamoyl-group,N-octylsulfamoyl group, N-2-ethylhexylsulfamoyl group, N-decylsulfamoylgroup, N-octadecylsulfamoyl group, N-phenylsulfamoyl group,N-2-methylphenylsulfamoyl group, N-2-chlorosulfamoyl group,N-2-methoxyphenylsulfamoyl group, N-2-isopropoxyphenylsulfamoyl group,N-2-(2-ethylhexyloxy) phenylsulfamoyl group, N-3-chlorophenylsulfamoylgroup, N-3-nitrophenylsulfamoyl group, N-3-cyanophenylsulfamoyl group,N-4-methoxysulfamoyl group, N-4-(2′-ethylhexyloxy) phenylsulfamoylgroup, N-4-cyanophenylsulfamoyl group, N-methyl-N-phenylsulfamoyl group,N,N-dimethylsulfamoyl group, N,N-dibutylsulfamoyl group,N,N-diphenylsulfamoyl group, N,N-di-(2-ethylhexyl) sulfamoyl group andthe like.

[0036] Alkylcarbonyl, arycarbonyl, alkoxycarbonyl and aryloxycarbonylgroups are included in examples of the substituted carbonyl grouprepresented by each of R² and R³.

[0037] Examples of the alkylcarbonyl group include an acetyl group,propanoyl group, butanoyl group, hexanoyl group, octanoyl group,2-ethylhexanoyl group, decanoyl group, dodecanoyl group, octadecanoylgroup, 2-cyanopropanoyl group, and 1,1-dimethylpropanoyl group and thelike.

[0038] Examples of the arylcarbonyl group include a benzoyl group,o-chlorobenzoyl group, p-chlorobenzoyl group, o-methoxyobenzoyl group,p-methoxyobenzoyl group, and o-methoxyobenzoyl group (toluoyl group).

[0039] Examples of the alkoxycarbonyl group include a methoxycarbonylgroup, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonylgroup, hexyloxycarbonyl group, 2-ethylhexyloxycarbonyl group,octyloxycarbonyl group, decyloxycarbonyl group, octadecyloxycarbonylgroup, phenyloxyethyloxycarbonyl group, phenyloxypropylcarbonyl group,2,4-di-t-amylphenyloxyethylcarbonyl group,2,6-di-t-methylcyclohexyloxycarbonyl group, isostearyloxycarbonyl groupand the like.

[0040] Examples of the aryloxycarbonyl group include a2-methylphenyloxycarbonyl group, 2-chlorophenyloxycarbonyl group,2,6-dimethylphenyloxycarbonyl group, 2,4,6-trimethylphenyloxycarbonylgroup, 2-methoxyphenyloxycarbonyl group, 2-butoxyphenyloxycarbonylgroup, 3-cyanophenyloxycarbonyl group, 3-nitrophenyloxycarbonyl group,2,2-ethylhexylphenyloxycarbonyl group, 3-(2-ethylhexyloxy)phenyloxycarbonyl group, 4-fluorophenyloxycarbonyl group,4-chlorophenyloxycarbonyl group, 4-cyanophenyloxycarbonyl group,4-butoxyphenyloxycarbonyl group and the like.

[0041] N-alkylcarbamoyl, N-arylcarbamoyl, N,N-dialkylcarbamoyl,N,N-diarylcarbamoyl, N-alkyl-N-arylcarbamoyl groups and the like areincluded in examples of the carbamoyl group, in addition to carbamoylgroups.

[0042] Examples of the carbamoyl group include an N-methylcarbamoylgroup, N-ethylcarbamoyl group, N-propylcarbamoyl group, N-butylcarbamoylgroup, N-hexylcarbamoyl group, N-cyclohexylcarbamoyl group,N-octylcarbamoyl group, N-2-ethylhexylcarbamoyl group, N-decylcarbamoylgroup, N-octadecylcarbamoyl group, N-phenylcarbamoyl group,N-2-methylphenylcarbamoyl group, N-2-chlorophenylcarbamoyl group,N-2-methoxyphenylcarbamoyl group, N-2-isopropoxyphenylcarbamoyl group,N-2-(2-ethylhexyloxy) phenylcarbamoyl group, N-3-chlorophenylcarbamoylgroup, N-3-nitrophenylcarbamoyl group, N-3-cyanophenylcarbamoyl group,N-4-methoxycarbamoyl group, N-4-(2′-ethylhexyloxy) phenylcarbamoylgroup, N-4-cyanophenylcarbamoyl group, N-methyl-N-phenylcarbamoyl group,N,N-dimethylcarbamoyl group, N,N-dibutylcarbamoyl group,N,N-diphenylcarbamoyl group and the like.

[0043] Examples of the halogen atom that can be represented by each ofR² and R³ include a fluorine atom, chlorine atom, bromine atom, and thelike and fluorine and chlorine atoms are preferred.

[0044] Among the groups described above, R¹ is particularly preferably ahydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an arylgroup having 6 to 10 carbon atoms.

[0045] Preferably, R² and R³ each represents a hydrogen atom, an alkylgroup having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbonatoms, analkylsulfonyl group having 1 to 10 carbon atoms, anarylsulfonyl group having 6 to 10 carbon atoms, a sulfamoyl group having1 to 10 carbon atoms, an alkylcarbonyl group having 1 to 10 carbonatoms, an arylcarbonyl group having 6 to 10 carbon atoms, analkoxycarbonyl group having 2 to 20 carbon atoms, a carbamoyl grouphaving 1 to 10 carbon atoms, or a cyano group.

[0046] In the general formulas (2) to (4), R⁴ and R⁶ each independentlyrepresents an alkyl group or an aryl group.

[0047] Alkyl groups having a substituent and non-substituted alkylgroups are included in examples of the alkyl group represented by eachof R⁴and R⁶. The alkyl group is preferably an alkyl group having 1 to 18carbon atoms. In cases where R⁴ and R⁶ represent alkyl groups having asubstituent, examples of the substituent include an alkoxy group, arylgroup, aryloxy group, alkylthio group, arylthio group, dialkylaminogroup and the like.

[0048] In a case where R⁴ represents an alkyl group, the alkyl group ispreferably a methyl group, an ethyl group, an n-propyl group, an n-butylgroup, an isobutyl group, an n-amyl group, a hexyl group, a heptylgroup, an n-octyl group, a 2-ethyl-hexyl group, a nonyl group, a decylgroup, a hexadecyl group, a 2-methoxyethyl group, a benzyl group or thelike. In a case where R⁶ represents an alkyl group, the alkyl group ispreferably a methyl group, an ethyl group, an n-propyl group, an n-butylgroup, an isobutyl group, an n-amyl group, an isoamyl group, a hexylgroup, a heptyl group, an n-octyl group, a 2-ethyl-hexyl group, a nonylgroup, a decyl group, a hexadecyl group, a 2-methoxyethyl group, anethoxycarbonylmethyl group, a 2-ethyl-hexylcarbonylmethyl group, anaminocarbonylmethyl group, an N,N-dimethylaminocarbonylmethyl group, anN-methylaminocarbonylmethyl group, an isopropyloxyethyl group, abutoxyethyl group, a phenoxyethyl group, a cyanomethyl group, a3,7-dimethyl-octyl group, a 3,5,5-trimethyl-hexyl group, a benzyl groupor the like. Alkyl and alkoxyethyl groups are preferred, and branchedalkyl and alkoxyethyl groups are particularly preferred.

[0049] Aryl groups having a substituent and non-substitutedaryl groupsare included in examples of the aryl group represented by each of R⁴andR⁶. The aryl group is preferably an aryl group having 6 to 30 carbonatoms. In cases where R⁴ and R⁶ represent aryl groups having asubstituent, examples of the substituent include an alkoxy group, nitrogroup, alkyl group and the like.

[0050] In a case where R⁴ represents an aryl group, the aryl group ispreferably a phenyl group, a 4-nitro-phenyl group, a 2-naphthyl group orthe like. In a case where R⁶ represents an aryl group, the aryl group ispreferably a phenyl group, a 2-methylphenyl group, a 3-methyl-phenylgroup, a 4-methoxy-phenyl group, a 2-naphthyl group or the like.

[0051] In the general formula (2), R⁵ represents an alkyl group, an arylgroup, or a heterocyclic group.

[0052] Alkyl groups having a substituent and non-substituted alkylgroups are included in examples of the alkyl group represented by R⁵.Examples of substituents include those mentioned as substituents of thealkyl group represented by each of R⁴ and R⁶. The alkyl grouprepresented by R⁵is preferably an alkyl group having 1 to 18 carbonatoms, and particularly preferably a methyl group, an ethyl group, ann-propyl group, an n-butyl group, an isobutyl group, an n-amyl group, ahexyl group, a heptyl group, an n-octyl group, a 2-ethyl-hexyl group, anonyl group, a decyl group, a hexadecyl group, a 2-methoxyethyl group, abenzyl group or the like.

[0053] Aryl groups having a substituent and non-substituted aryl groupsare included in examples of the aryl group represented by R⁵. Examplesof substituents include those mentioned as substituents of the arylgroup represented by each of R⁴ and R^(6.) The alkyl group representedby R⁵ is preferably an aryl group having 6 to 30 carbon atoms, andparticularly preferably a phenyl group, a 4-nitro-phenyl group, a2-naphthyl group or the like.

[0054] Heterocyclic groups having a substituent and non-substitutedheterocyclic groups are included in examples of the heterocyclic grouprepresented by R⁵. The heterocyclic group may contain a saturatedheterocycle or an unsaturated heterocycle. The heterocyclic group isparticularly preferably a 2-pyridyl group, a 4-pyridyl group, a2-pyrimidyl group, a methyl-tetrazoyl group, an ethyl-triazoyl group, abenzothiazoyl group, a benzoxazoyl group or the like.

[0055] The aminopyrrole derivative represented by the general formula(1) can be synthesized by conventionally known procedures described inU.S. Pat. Nos. 3,836,541, 3,838,166, “Synthesis”, 1, 51 (1976), and thelike.

[0056] Specific examples of the aminopyrrole derivative represented bythe general formula (1) (exemplified compounds (1-1) to (1-27)) areshown below, but the present invention is not limited by the followingspecific examples. General formula (1)

R¹ R² R³ 1-1 —H —C₆H₅ —H 1-2 —H —C₆H₅ —CN 1-3 —H —C₆H₅ —CO₂C₂H₅ 1-4 —H—C₆H₅

1-5 —H

—CN 1-6 —H

1-7 —H

—CN 1-8 —H

1-9 —H

1-10 —H

1-11 —H

1-12 —H —CN —CN 1-13 —H —CO₂C₂H₅ —CO₂C₂H₅ 1-14 —H —CN —C₆H₅ 1-15 —H—C₆H₅ —C₆H₅ 1-16 —CH₃ —C₆H₅ —CN 1-17

—C₆H₅ —CN 1-18 —H —C₆H₅ —SO₂C₈H₁₇ 1-19 —H —C₆H₅ —SO₂C₆H₅ 1-20 —H —C₆H₅—CN 1-21 —H —C₆H₅ —CN 1-22 —H —C₆H₅

1-23 —H

1-24 —Cl —C₆H₅ —CN 1-25 —OCH₃ —C₆H₅ —CN 1-26 —OC₆H₅

—CN 1-27 —SC₄H₉ —C₆H₅ —CN

[0057] Specific examples of the reactant represented by the generalformula (2) (exemplified compounds (2-1) to (2-35)) are shown below, butthe present invention is not limited by the following specific examples.

[0058] Specific examples of an adduct represented by general formula (3)(exemplified compounds (3-1) to (3-21)) are shown below, but the presentinvention is not limited by the following specific examples. Generalformula (3)

R¹ R² R³ 3-1 —H —C₆H₅

3-2 —H

3-3 —H

3-4 —H —C₆H₅ —CN 3-5 —Cl —C₆H₅

3-6 —Cl

3-7 —OCH₃

—CN 3-8

—C₆H₅

3-9 —H

3-10 —H

3-11 —H

3-12 —CH₃ —CH₃ —CO₂C₂H₅ 3-13 —H

—CO₂C₂H₅ 3-14 —H

—CO₂C₂H₅ 3-15 —H

—CO₂C₂H₅ 3-16 —H —CO₂C₂H₅ —CO₂C₂H₅ 3-17 —H

3-18 —H —CN

3-19 —H —C₆H₅

3-20 —H

—CO₂C₂H₅ 3-21 —SCH₃

—SO₂CH₃ R⁴ R⁶ 3-1 —C₂H₅ —CH₃ 3-2 —C₂H₅ —CH₃ 3-3 —CH₃ —CH₃ 3-4 —C₂H₅—C₂H₅ 3-5 —C₂H₅

3-6 —C₂H₅

3-7 —C₂H₅

3-8 —CH₃

3-9 —C₂H₅

3-10 —CH₃

3-11 —C₂H₅

3-12

—C₁₀H₂₁ 3-13

—C₄H₉(n) 3-14 —C₂H₅

3-15 —CH₃

3-16 —C₂H₅ —C₂H₅ 3-17 —CH₃

3-18 —C₂H₅

3-19 —C₂H₅

3-20 —C₂H₅

3-21

—C₂H₅

[0059] Specific examples of the pyrrolotriazin-4-one compoundrepresented by the general formula (4) (exemplified compounds (4-1) to(4-21)), which can be prepared by the preparation method of the presentinvention, are shown below, but the present invention is not limited bythe following specific examples. General formula (4)

R¹ R² R³ R⁶ 4-1 —H —C₆H₅

—CH₃ 4-2 —H

—CH₃ 4-3 —H

—CH₃ 4-4 —H —C₆H₅ —CN —C₂H₅ 4-5 —Cl —C₆H₅

4-6 —Cl

4-7 —OCH₃

—CN

4-8

—C₆H₅

4-9 —H

4-10 —H

4-11 —H

4-12 —CH₃ —CH₃ —CO₂C₂H₅ —C₁₀H₂₁ 4-13 —H

—CO₂C₂H₅ —C₄H₉(n) 4-14 —H

—CO₂C₂H₅

4-15 —H

—CO₂C₂H₅

4-16 —H —CO₂C₂H₅ —CO₂C₂H₅ —C₂H₅ 4-17 —H

4-18 —H —CN

4-19 —H —C₆H₅

4-20 —H

—CO₂C₂H₅

4-21 —SCH₃

—SO₂CH₃ —C₂H₅

[0060] A scheme of the preparation method of the present invention isshown below.

[0061] Method of Preparing Isothiocyanatoformic Acid Ester Derivative

[0062] First, a method of preparing an isothiocyanatoformic acid esterderivative of the present invention will be described. Theisothiocyanatoformic acid ester derivative can be prepared by thefollowing preparation scheme.

[0063] Step [1]

[0064] As shown in the scheme above, the isothiocyanatoformic acid esterderivative of the present invention can be prepared by the step [1], offorming an intermediate represented by general formula (8), step [2],forming an intermediate represented by the general formula (10), andstep [3], forming the isothiocyanatoformic acid ester derivativerepresented by the general formula (2).

[0065] These three steps are not necessarily required and theisothiocyanatoformic acid ester derivative can also be prepared usingonly one of the steps [1], [2] and [3] or two steps selected from thethree steps described above in combination with a known step. To obtainthe isothiocyanatoformic acid ester derivative, which is preferably usedas a reactant for a pyrrolotrizinone compound, with high yield and highpurity, all three steps described above are preferably used.

[0066] The respective steps will be described below.

[0067] Step [1]

[0068] The step [1] is a step of preparing the intermediate representedby the general formula (8) by adding an isothiocyanic acid saltrepresented by general formula (5) a hydroxy derivative represented bygeneral formula (6), and further adding a chloroformic acid derivativerepresented by general formula (7).

[0069] In the general formula (5), Z represents a sodium atom or apotassium atom. In the general formulas (6), (7) and (8), R⁴ and R⁶ areas defined for the general formula (2).

[0070] An amount (mol) of the isothiocyanic acid salt represented by thegeneral formula (5) is preferably 1-5 times, and more preferably 1-3times, an amount of the chloroformic acid derivative represented by thegeneral formula (6).

[0071] An amount (mol) of the hydroxy derivative represented by thegeneral formula (7) is preferably 0.5-3 times, and more preferably0.5-1.5 times, an amount of the chloroformic acid derivative representedby the general formula (6).

[0072] In the step [1], the intermediate represented by the generalformula (8) can be prepared by dissolving the isothiocyanic acid saltrepresented by the general formula (5) and the hydroxy derivativerepresented by the general formula (6) in a reaction solvent, and addingthe chloroformic acid derivative represented by the general formula (7)dropwise, thus causing a reaction.

[0073] Suitable examples of the reaction solvent include acetonitrile,acetone, tetrahydrofuran and the like. Among these reaction solvents,acetonitrile and acetone are preferred.

[0074] The reaction temperature in the step [1] is preferably from −25to 40° C., and more preferably from −5 to 25° C.

[0075] In the step [1] an isothiocyanatoformic acid ester (R⁴OOCNCS)formed by the reaction between the isothiocyanic acid salt representedby the general formula (5) and the chloro formic acid derivativerepresented by the general formula (6) reacts with the hydroxyderivative represented by the general formula (7) immediately, becauseof prior colocalization of the isothiocyanic acid salt represented bythe general formula (5) and the hydroxy derivative represented by thegeneral-formula (6). Therefore, decomposition of theisothiocyanatoformic acid ester (R⁴OCNCS)is prevented. As a result, theyield of the intermediate represented by the general formula (8) isenhanced as compared with a conventional preparation method.

[0076] Step [2]

[0077] The step [2] is a step of preparing the intermediate representedby the general formula (10) from the intermediate represented by thegeneral formula (8) and a compound represented by general formula (9).

[0078] In the general formula (9), M represents an alkali metal atom, analkali earth metal atom, an aluminum atom, or a magnesium atom. In thegeneral formula (10), R⁴ and R⁶ are as defined for the general formula(2).

[0079] The alkali metal atom is preferably a lithium atom, a sodiumatom, a potassium atom, or a cesium atom.

[0080] The alkali earth metal atom is preferably a calcium atom or abarium atom.

[0081] In the step [2], the intermediate represented by the generalformula (10) can be prepared by dissolving the compound represented bythe general formula (9) in a reaction solvent, and adding theintermediate represented by the general formula (8), thus precipitatingthe intermediate represented by the general formula (10) as crystals.

[0082] Suitable examples of the reaction solvent include water,methanol, ethanol, acetonitrile, acetone, tetrahydrofuran and the like.Among these reaction solvents, methanol and ethanol are preferred.

[0083] An amount (mol) of the compound represented by the generalformula (9) is preferably 1-5 times-an amount of the intermediaterepresented by the general formula (8).

[0084] To accelerate crystallization, a compound represented by generalformula MY (M is as defined for the general formula (9), and Yrepresents a halogen atom) may be added. An amount (mol) of the compoundrepresented by the general formula MY is preferably 1-10 times theamount of the intermediate represented by the general formula (8).

[0085] In the step [2], the compound represented by the general formula(10) can be obtained as crystals by reacting the intermediaterepresented by the general formula (8) with the compound represented bythe general formula (9), and can be purified by means ofrecrystallization or the like.

[0086] Step [3]

[0087] The step [3] is a step of preparing the isothiocyanatoformic acidester derivative represented by the general formula (2) by reacting theintermediate represented by the general formula (10) with an alkylatingagent represented by general formula (11) or (12).

[0088] In the general formula (11), X represents a halogen atom orSO₃Ar. Ar represents a substituted or non-substituted aryl group.

[0089] Preferred examples of the halogen atom include a chloride atom, abromine atom, and an iodine atom.

[0090] In the general formulas (11) and (12), R⁵ is as defined for thegeneral formula (2).

[0091] An amount (mol) of the alkylating agent represented by thegeneral formulas (11) and (12) is preferably 1-3 times, and morepreferably 1-1.5 times, an amount of the intermediate represented by thegeneral formula (10).

[0092] In the step [3], the isothiocyanatoformic acid ester derivativerepresented by the general formula (2) can be prepared by suspending theintermediate represented by the general formula (10) in a reactionsolvent, and adding the alkylating agent represented by the generalformulas (11) or (12) dropwise.

[0093] Suitable examples of the reaction solvent include acetonitrile,acetone, dimethylformamide, dimethylacetylamide, tetrahydrofuran,dimethyl sulfoxide, and alcohol (e.g. methanol, ethanol, isopropanol,propanol, n-butanol, t-butanol, etc.). Among these reaction solvents,acetonitrile, ethyl acetate, butyl acetate, benzene, toluene,dimethylformamide, dimethylacetylamide, tetrahydrofuran, and dimethylsulfoxide are preferred.

[0094] The reaction temperature in the step [3] is preferably from −25to 40° C., and more preferably from −5 to 25° C.

[0095] A method of synthesizing the pyrrolotriazinone compound in thepresent invention will be described below. The pyrrolotriazinonecompound can be prepared through the following preparation scheme.

[0096] Respective steps will be described below.

[0097] Addition Step

[0098] The addition step is a step of reacting the aminopyrrolederivative represented by the general formula (1) with the reactantrepresented by the general formula (2) to form the adduct represented bythe general formula (3). For example, a reaction can be caused toproceed by uniformly dissolving or suspending the aminopyrrolederivative represented by the general formula (1) and the reactantrepresented by the general formula (2), optionally adding an acid, andheating.

[0099] The reaction temperature in the addition step is preferably notless than −5° C. and not more than the boiling point of a solvent beingused, and more preferably not less than 30° C. and not more than 80° C.in view of ease of operation.

[0100] The aminopyrrole derivative represented by the general formula(1) is preferably dissolved in a 1.0- to 50-fold amount (by weight) ofan organic solvent, and more preferably dissolved in a 5.0- to 30-foldamount (by weight) of the organic solvent.

[0101] The organic solvent used in the addition step is preferably inertwith respect to the reactant represented by the general formula (2), andis preferably anhydrous. Examples of the organic solvent includeacetonitrile, acetone, ethyl acetate, butyl acetate, benzene, toluene,dimethylformamide, dimethylacetylamide, tetrahydrofuran, dimethylsulfoxide, and alcohol (e.g. methanol, ethanol, isopropanol, propanol,n-butanol, t-butanol, etc.) . Among these organic solvents,acetonitrile, acetone, tetrahydrofuran, ethyl acetate, butyl acetate,and toluene are preferred.

[0102] In the addition step, an amount (mol) of the reactant representedby the general formula (2)-is preferably 1.0-5.0 times, and morepreferably 1.0-2.0 times, an amount of the aminopyrrole derivativerepresented by the general formula (1).

[0103] In the addition step, the reaction can be accelerated if an acidor a salt thereof or a base is allowed to exist in the reaction, whichis preferable. Examples of the acid or salt thereof include substitutedor non-substituted alkylcarboxylic acid (preferably C₁₋₁₈alkylcarboxylic acid) and salts thereof (alkali metal or alkali earthmetal, such as Na, K, etc.); substituted or non-substitutedarylcarboxylic acid (preferably C₆₋₃₅ alkylcarboxylic acid) and saltsthereof (alkali metal or alkali earth metal, such as Na, K, etc.);substituted or non-substituted alkylsulfonic acid (preferably C₁₋₁₈,alkylsulfonic acid) and salts thereof (alkali metal or alkali earthmetal, such as Na, K, etc., or an organic base such aspyridinetriethylamine, 1,8-diazobicyclo[5.4.0]undece-7-ene (DBU), etc.);substituted or non-substituted arylsulfonic acid (preferably C₆₋₃₅arylsulfonic acid) and salts thereof (alkali metal or alkali earthmetal, such as Na, K, etc., an organic base such aspyridinetriethylamine, DBU, etc.); and Lewis acids (e.g. BF₄, ZnCl₂,ZnCl₄, AlCl₃, etc.). Examples of the base include organic bases (e.g.triethylamine, DBU, etc.), hydride (e.g. NaH, KH, CaH₂, etc.),andalcoholates (e.g. NaOMe, NaOEt, KO(t)Bu, etc.).

[0104] Among these, an acid is preferred. Among acids, a substituted ornon-substituted alkylcarboxylic acid (preferably C₁₋₁₈ alkylcarboxylicacid), a substituted or non-substituted arylcarboxylic acid (preferablyC₆₋₃₅ alkylcarboxylic acid), a substituted or non-substitutedalkylsulfonic acid (preferably C₁₋₁₈ alkylsulfonic acid), and asubstituted or non-substituted arylsulfonic acid (preferably C₆₋₃₅arylsulfonic acid) are preferred, and trifluoroacetic acid andmethanesulfonic acid are particularly preferred.

[0105] The amount of the acid or salt thereof or base is preferably notless than 0.1 mmol and not more than 3.0 mmol, and more preferably notless than 0.1 mmol and not more than 1.0 mmol, for 1.0 mol of theaminopyrrole derivative represented by the general formula (1). Theseacids or salts thereof or bases may be used alone or in a combinationthereof. When using two or more kinds thereof, the total amount thereofis preferably within the range described above.

[0106] Preferably, when using the acid or salt thereof or base, the acidis uniformly dissolved or suspended in a solvent, together with theaminopyrrole derivative and the reactant.

[0107] After completion of the reaction, the adduct represented by thegeneral formula (3) can be obtained by removing by-products and solventfrom the resulting reaction mixture. Generally, substances formed asby-products in the addition step are slightly soluble. Thus, the adductcan be purified by recrystallizing from a suitable solvent, making useof a difference in solubility in an organic solvent between theby-products and the adduct.

[0108] The adduct can be transferred to the following cyclization stepas is without being isolated from a reaction system.

[0109] Cyclization Step

[0110] In the cyclization step, the adduct represented by the generalformula (3) is cyclized to form the pyrrolotriazin-4-one represented bythe general formula (4). For example, a reaction can be caused toproceed by uniformly dissolving the adduct represented by the generalformula (3) in a solvent, optionally adding an acid, and then heating.

[0111] The reaction temperature in the cyclization step is preferablynot less than −5° C. and not more than the boiling point of the solventbeing used, and more preferably not less than 10° C. and not more than85° C. in view of ease of operation.

[0112] The adduct represented by the general formula (3) is preferablydissolved in a 1.0- to 50-fold amount (by weight) of an organic solvent,and more preferably dissolved in a 5.0- to 30-fold amount (by weight) ofthe organic solvent.

[0113] Examples of the organic solvent include acetonitrile, acetone,ethyl acetate, butyl acetate, benzene, toluene, dimethylformamide,dimethylacetylamide, tetrahydrofuran, dimethyl sulfoxide, and alcohol(e.g. methanol, ethanol, isopropanol, propanol, n-butanol, t-butanol,etc.). Among these organic solvents, acetonitrile, acetone,tetrahydrofuran, methanol, ethanol, isopropanol, propanol and the likeare preferred.

[0114] In a case where the adduct represented by the general formula (3)is transferred to the cyclization step without isolation, the sameorganic solvent as that used in the addition step can be used. Forexample, acetonitrile, acetone and tetrahydrofuran are organic solventswhich can be preferably used in both steps.

[0115] In the cyclization step, the reaction can be accelerated if anacid or a salt thereof or a base is allowed to exist in the reaction,which is preferable. Examples of the acid or salt thereof includesubstituted or non-substituted alkylcarboxylic acid (preferably C₁₋₁₈alkylcarboxylic acid) and salts thereof (alkali metal or alkali earthmetal, such as Na, K, etc., or an organic base such aspyridinetriethylamine, DBU, piperidine, etc.); substituted ornon-substituted alkylsulfonic acid (preferably C₁₋₁₈ alkylsulfonic acid)and salts thereof (alkali metal or alkali earth metal, such as Na, K,etc., or an organic base such as pyridinetriethylamine, DBU, etc.);substituted or non-substituted arylsulfonic acid (preferably C₆₋₃₅arylsulfonic acid) and salts thereof (alkali metal or alkali earthmetal, such as Na, K, etc., or an organic base such aspyridinetriethylamine, DBU, etc.); and Lewis acids (e.g. BF₄, ZnCl₂,ZnCl₄, AlCl₃, etc.). Examples of the base include organic bases (e.g.triethylamine, DBU, etc.), hydride (e.g. NaH, KH, CaH₂, etc.), andalcoholates (e.g. NaOMe, NaOEt, KO(t)Bu, etc.).

[0116] Among these, an organic base (e.g. triethylamine, DBU, etc.), analcoholate (e.g. NaOMe, NaOEt, KO(t)Bu, etc.), or a substituted ornon-substituted alkylcarboxylic acid or a salt thereof (e.g. aceticacid, potassium acetate, sodium acetate, piperidine acetate, etc.) ispreferred.

[0117] The amount of the acid or salt thereof or base is preferably notless than 0.1 mol and not more than 3.0 mol for 1.0 mol of the adductrepresented by the general formula (3). These acids or salts thereof orbases may be used alone or in a combination thereof. When using two ormore kinds thereof, the total amount thereof is preferably within therange described above.

[0118] In a case where the adduct represented by the general formula (3)is transferred to the cyclization step without being isolated, the acidor salt thereof or base is added to a reaction mother liquor of in theaddition step after completion of the addition reaction. In this case,the acid or salt thereof or base is preferably added an amount of notless than 1.0 mol and not more than 3.0 mol, based on a stock amount ofthe aminopyrrole derivative represented by the general formula (1).

[0119] After completion of the cyclization reaction, the reactionmixture is cooled, thereby making it possible to precipitate thepyrrolotriazin-4-one compound represented by the general formula (4) andto isolate the same by filtration or the like. Crude crystals obtainedby filtration can be purified by recrystallizing from a suitablesolvent.

EXAMPLES

[0120] The following Examples further illustrate the present inventionin detail, but the present invention is not limited by these Examples.

Example 1

[0121] Preparation Example of exemplified compound (2-1), anisothiocyanatoformic acid ester derivative

[0122] The exemplified compound (2-1) and Preparation Example thereofare shown below.

[0123] 1) Preparation of Intermediate (10-1)

[0124] 48.5 g (0.5 mol) of potassium isothiocyanate (KNCS) and 71 g(0.45 mol) of tetrahydrogeraniol (3,7-dimethyl-1-octanol) were dissolvedin 250 ml of acetone. The solution was cooled to an inner temperature of5° C., and then 48.5 g (0.45 mol) of ethyl chloroformate was addeddropwise over one hour such that the inner temperature did not rise to15° C. or higher. A reaction proceeded for three hours with the reactionsolution in the cooled state, the inner temperature was then returned toroom temperature, and the solution was left to stand for 24 hours.

[0125] Then, 94 g (0.3 mol) of a barium hydroxide (Ba(OH)₂) hydrate wasdissolved in 500 ml of water, the reaction solution was added to thisaqueous solution, and crystals were precipitated. The resulting crystalswere collected by filtration and then washed with water until an alkalicomponent was removed. After drying, 114 g (0.16 mol) of intermediate(10-1) was obtained as white crystals.

[0126] The yield of the intermediate (10-1) was 71%, calculated in termsof tetrahydrogeraniol.

[0127] The purity of the intermediate (10-1) was measured by gaschromatography, and was at least 98%.

[0128] The intermediate (10-1) was neutralized to form an intermediate(8-1), and then structural analysis was conducted by ¹H-NMR (solvent:CDCl₃, 300MHz, TMS standard). Results data are shown below.

[0129]¹H-NMR [δ, ppm]: 8.13 (1H, NH), 4.58 (2H, —OCH₂CH₂), 4.21 (2H,—OCH₂CH₃), 2.37 (3H, —SCH₃)

[0130] 2) Preparation of Exemplified Compound (2-1)

[0131] 75 g (0.115 mol) of the intermediate (10-1) obtained in 1) wasdissolved in acetone. This reaction solution was cooled to 15° C., andthen 30 g (0.24 mol) of dimethylsulfuric acid serving as an alkylatingagent was added dropwise over 15 minutes. Thereafter, a reaction wasconducted for one hour, and then the reaction solution was filtered toremove an inorganic component. The resulting filtrate was concentratedunder reduced pressure and this concentrate was extracted by adding 100ml of ethyl acetate and 100 ml of water. An organic layer wasconcentrated under reduced pressure to obtain 64 g (0.21 mol) of theexemplified compound (2-1) of the isothiocyanatoformic acid esterderivative as a light yellow oily component.

[0132] The yield of the exemplified compound (2-1) was 91%.

[0133] The purity of the exemplified compound (2-1) was measured by gaschromatography, and was 98%.

[0134] Structural analysis of the exemplified compound (2-1) wasconducted by ¹H-NMR (solvent: CDCl₃, 300 MHz, TMS standard). Resultsdata are shown below. ¹H-NMR (δ, ppm) : 4.36 (2H, —OCH₂CH₂), 4.23 (2H,—OCH₂CH₃), 2.37 (3H, —SCH₃)

[0135] Comparative Example 1

[0136] Preparation Example of comparative compound (2′-1), anisothiocyanatoformic acid ester derivative

[0137] The exemplified compound (2′-1) and Preparation Example thereofare shown below.

[0138] 1) Preparation of Intermediate (8′-1)

[0139] 48.5 g (0.5 mol) of potassium isothiocyanate (KNCS) was dissolvedin 250 ml of acetone. This solution was cooled to an inner temperatureof 5° C., and then 48.5 g (0.45 mol) of ethyl chioroformate (ClCOOC₂H₅)was added dropwise over one hour such that the inner temperature did notrise to 15° C. or higher. Thereafter, 71 g (0.45 mol) oftetrahydrogeraniol was added to the reaction solution and the solutionwas left to stand at room temperature for 24 hours. 5 g of activatedcarbon was added to the reaction solution and the solution, was filteredto remove the activated carbon and an inorganic component. The resultingfiltrate was concentrated under reduced pressure to obtain 95 g of anintermediate (8′-1) as a yellow oily product.

[0140] The purity of the intermediate (8′-1) was measured by gaschromatography, and was 55%.

[0141] 2) Preparation of Comparative Compound (2′-1)

[0142] 95 g (0.33 mol) of the intermediate (8′-1) obtained in 1) and 50g (1.36 mol) of potassium carbonate were dissolved in 500 ml of acetone.This reaction solution was cooled to 15° C., and then 46 g (0.36 mol) ofdimethylsulfuric acid serving as an alkylating agent was added dropwiseover 30 minutes. Thereafter, a reaction was conducted for two hours, andthen the reaction solution was filtered to remove an inorganiccomponent. The resulting filtrate was concentrated under reducedpressure and this concentrate was extracted by adding 500 ml of ethylacetate and 500 ml of water. An organic layer was concentrated underreduced pressure to obtain 90 g of the comparative compound (2′-1) ofthe isothiocyanatoformic acid ester derivative as a light yellow oilycomponent.

[0143] The purity of the comparative compound (2′-1) was measured by gaschromatography, and was 40%.

[0144] It was confirmed from the results described above thatwith thepreparation method of the present invention, an isothiocyanatoformicacid ester derivative can be prepared at higher yield and higher puritythan with the preparation method of the Comparative Example.

Example 2 Synthesis of Exemplified Compound (4-9)

[0145] To a reaction solution prepared by suspending 85 g (0.19 mol) ofan aminopyrrole, exemplified compound (1-6), and 71 g (0.22 mol) of theexemplified compound (2-1) in 150 ml of acetonitrile, 0.5 g (5 mmol) ofmethanesulfonic acid was added. Then the reaction solution was heated to55-60° C. and further stirred for 24 hours.

[0146] 20 ml of acetic acid was added to the reaction solution, and then15 g of 28% sodium methoxide was added. Then the reaction solution washeated to 55-60° C. and further stirred for six hours. The reactionsolution was cooled to 10° C.-15° C. and stirred for one hour. Crystalsprecipitated from the reaction solution were filtered and recrystallizedfrom ethanol to obtain 51 g (yield: 47%) of the exemplified compound(4-9) as white crystals.

[0147] Data (δ, ppm) of ¹H-NMR (solvent: CDCl₃, TMS standard, 300 MHz)for the resulting compound were:

[0148] 10.4 (s, 1H), 7.2-7.45 (m, 5H), 5.85 (s, 1H), 4.6 (m, 2H)

Example 3 Synthesis of Exemplified Compound (4-2)

[0149] To a reaction solution prepared by suspending 80 g (0.18 mol) ofthe aminopyrrole, exemplified compound (1-6), and 42 g (0.237 mol) ofthe exemplified compound (2-4) in 200 ml of acetonitrile, 0.5 g (5 mmol)of methanesulfonic acid was added. Then the reaction solution was heatedto 55-60° C. and further stirred for 24 hours. The reaction solution wascooled to room temperature and precipitated crystals were filtered. Theresulting crude crystals were recrystallized from ethanol to obtain 75 g(yield: 73%) of the exemplified compound (3-2) as light yellow crystals.

[0150] Data (δ, ppm) of ¹H-NMR (solvent: CDCl₃, TMS standard, 300 MHz)for the resulting compound were:

[0151] 9.3 (s, 1H), 7.2-7.37 (m, 4H), 6.25 (d, 1H), 5.85 (s, 1H), 4.3(q, 2H), 4.15 (s, 3H), 1.35 (t, 3H)

[0152] To a suspension prepared by suspending 65 g (0.114 mol) of theresulting exemplified compound (3-2) in 200 ml of ethanol, 25 g (0.13mol) of 28% sodium methoxide was added. Then the suspension was heatedto 35-40° C. and further stirred for one hour. Water was poured intothis reaction solution and this solution was neutralized withhydrochloric acid. Then, after extracting with 300 ml of ethyl acetate,an organic layer was concentrated under reduced pressure. To thissolidified concentrate, 250 ml of methanol was added, after whichheating at reflux was performed for one hour. After cooling to roomtemperature, precipitated crystals were filtered to obtain 48 g (yield:80%) of an exemplified compound (4-2) as white crystals.

[0153] Data (δ, ppm) of ¹H-NMR (solvent: CDCl₃, TMS standard, 300 MHz)for the resulting compound were:

[0154] 10.2 (δ, 1H), 7.2-7.4 (m, 5H), 5.9 (s, 1H), 4.17 (s, 3H)

[0155] With the present invention, a pyrrolotriazin-4-one compound canbe prepared at high yield by a simple operation. Also, with the presentinvention, a novel isothiocyanatoformic acid ester derivative, which canbe used preferably as a reactant for synthesis of a pyrrolotriazinonecompound, can be provided, and a method of preparing theisothiocyanatoformic acid ester derivative at high purity and high yieldcan be provided.

What is claimed is:
 1. A method of preparing a pyrrolotriazin-4-onecompound represented by the following general formula (4), the methodcomprising: an addition step of reacting an aminopyrrole derivativerepresented by the following general formula (1) with a reactantrepresented by the following general formula (2) for forming an adductrepresented by the following general formula (3); and a cyclization stepof cyclizing the adduct represented by the following general formula (3)for forming the pyrrolotriazin-4-one represented by the followinggeneral formula (4),

wherein, in the general formulas, R¹ represents a hydrogen atom, analkyl group, an aryl group, or a group capable of withdrawing; R² and R³each independently represents a hydrogen atom, an alkyl group, an arylgroup, a cyano group, a substituted sulfonyl group, a substitutedcarbonyl group, or a halogen atom; R⁴ represents a substituted ornon-substituted alkyl group, or a substituted or non-substituted arylgroup; R⁵ represents a substituted or non-substituted alkyl group, asubstituted or non-substituted aryl group, or a substituted ornon-substituted heterocyclic group; and R⁶ represents a substituted ornon-substituted alkyl group having at least 3 carbon atoms, or asubstituted or non-substituted aryl group.
 2. The method of preparing apyrrolotriazin-4-one according to claim 1, wherein at least one of afirst acid, a salt of the first acid, and a base is present in areaction system of the addition step.
 3. The method of preparing apyrrolotriazin-4-one according to claim 2, wherein the first acid is atleast one acid selected from the group consisting of alkylsulfonic acid,arylsulfonic acid, alkylcarboxylic acid and Lewis acid.
 4. The method ofpreparing a pyrrolotriazin-4-one according to claim 2, wherein the saltof the first acid is at least one salt of the acid selected from thegroup consisting of alkylsulfonic acid, arylsulfonic acid,alkylcarboxylic acid and Lewis acid.
 5. The method of preparing apyrrolotriazin-4-one according to claim 1, wherein at least one of asecond acid, a salt of the second acid, and a base is present in areaction system of the cyclization step.
 6. The method of preparing apyrrolotriazin-4-one according to claim 2, wherein at least one of asecond acid, a salt of the second acid, and a base is present in areaction system of the cyclization step.
 7. The method of preparing apyrrolotriazin-4-one according to claim 3, wherein at least one of asecond acid, a salt of the second acid, and a base is present in areaction system of the cyclization step.
 8. An isothiocyanatoformic acidester derivative represented by the following general formula (2):

in which: R⁴ represents a substituted or non-substituted alkyl group, ora substituted or non-substituted aryl group; R⁵ represents a substitutedor non-substituted alkyl group, a substituted or non-substituted arylgroup, or a substituted or non-substituted heterocyclic group; and R⁶represents a substituted or non-substituted alkyl group having at least3 carbon atoms, or a substituted or non-substituted aryl group.
 9. Amethod of preparing the isothiocyanatoformic acid ester derivativeaccording to claim 8, the method comprising the steps of: adding achloroformic acid derivative represented by the following generalformula (7) to an isothiocyanic acid salt represented by the followinggeneral formula (5) and a hydroxy derivative represented by thefollowing general formula (6) for preparing an intermediate representedby the following general formula (8); and preparing theisothiocyanatoformic acid ester derivative from the intermediate:

wherein, in the general formula (5), Z represents a sodium atom or apotassium atom.
 10. A method of preparing the isothiocyanatoformic acidester derivative according to claim 8, the method comprising the stepsof: preparing a first intermediate represented by the following generalformula (8); preparing a second intermediate represented by thefollowing general formula (10) from the first intermediate and acompound represented by the following general formula (9); and preparingthe isothiocyanatoformic acid ester derivative from the secondintermediate:

wherein, in the general formulas (9) and (10), M represents an alkalimetal atom, an alkali earth metal atom, an aluminum atom or a magnesiumatom.
 11. A method of preparing the isothiocyanatoformic acid esterderivative according to claim 8, the method comprising the steps of:preparing an intermediate represented by the following general formula(10); and reacting the intermediate with an alkylating agent representedby one of the following general formula (11) and the following generalformula (12) for preparing the isothiocyanatoformic acid esterderivative:

wherein, in the general formula (10), M represents an alkali metal atom,an alkali earth metal atom, an aluminum atom or a magnesium atom, and,in the general formula (11), X represents a halogen atom or SO₃Ar, andAr represents a substituted or non-substituted aryl group.
 12. A methodof preparing the isothiocyanatoformic acid ester derivative according toclaim 8, the method comprising the steps of: adding a chloroformic acidderivative represented by the following general formula (7) to anisothiocyanic acid salt represented by the following general formula (5)and a hydroxy derivative represented by the following general formula(6) for preparing a first intermediate represented by the followinggeneral formula (8); preparing a second intermediate represented by thefollowing general formula (10) from the first intermediate and acompound represented by the following general formula (9); and preparingthe isothiocyanatoformic acid ester derivative from the secondintermediate:

wherein, in the general formula (5), Z represents a sodium atom or apotassium atom, and, in the general formulas (9) and (10), M representsan alkali metal atom, an alkali earth metal atom, an aluminum atom or amagnesium atom.
 13. A method of preparing the isothiocyanatoformic acidester derivative according to claim 8, the method comprising the stepsof: preparing a first intermediate represented by the following generalformula (8); preparing a second intermediate represented by thefollowing general formula (10) from the first intermediate and acompound represented by the following general formula (9); and reactingthe second intermediate with an alkylating agent represented by one ofthe following general formula (11) and the following general formula(12) for preparing the isothiocyanatoformic acid ester derivative:

wherein, in the general formulas (9) and (10) , M represents an alkalimetal atom, an alkali earth metal atom, an aluminum atom or a magnesiumatom, and, in the general formula (11) , X represents a halogen atom orSO₃Ar, and Ar represents a substituted or non-substituted aryl group.14. A method of preparing the isothiocyanatoformic acid ester derivativeaccording to claim 8, the method comprising the steps of: adding achloroformic acid derivative represented by the following generalformula (7) to an isothiocyanic acid salt represented by the followinggeneral formula (5) and a hydroxy derivative represented by thefollowing general formula (6) for preparing a first intermediaterepresented by the following general formula (8); preparing a secondintermediate represented by the following general formula (10) from thefirst intermediate; and reacting the second intermediate with analkylating agent represented by one of the following general formula(11) and the following general formula (12) for preparing theisothiocyanatoformic acid ester derivative:

wherein, in the general formula (5), Z represents a sodium atom or apotassium atom, in the general formula (10), M represents an alkalimetal atom, an alkali earth metal atom, an aluminum atom or magnesiumatom, and, in the general formula (11), X represents a halogen atom orSO₃Ar, and Ar represents a substituted or non-substituted aryl group.15. A method of preparing the isothiocyanatoformic acid ester derivativeaccording to claim 8, the method comprising the steps of: adding achloroformic acid derivative represented by the following generalformula (7) to an isothiocyanic acid salt represented by the followinggeneral formula (5) and a hydroxy derivative represented by thefollowing general formula (6) for preparing a first intermediaterepresented by the following general formula (8); preparing a secondintermediate represented by the following general formula (10) from thefirst intermediate and a compound represented by the following generalformula (9); and reacting the second intermediate with an alkylatingagent represented by one of the following general formula (11) and thefollowing general formula (12) for preparing the isothiocyanatoformicacid ester derivative:

wherein, in the general formula (5), Z represents a sodium atom or apotassium atom, in the general formulas (9) and (10), M represents analkali metal atom, an alkali earth metal atom, an aluminum atom or amagnesium atom, and, in the general formula (11), X represents a halogenatom or SO₃Ar, and Ar represents a substituted or non-substituted arylgroup.